Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study

Background Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12888-024-05764-6.


CYP2C19 NM vs. UM -Discontinuing Power calculation -Odds of discontinuing
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of discontinuing AD treatment (Y=1) when being a CYP2C19 NM patient (X=0): • Pr( = 1|  = 1)  0 =  1 Odds ratio (OR) being calculated according to the following formulas: Proportion of cases for which X=1 (CYP2C19 UM) within the total sample size (n=161): •    =     ℎℎ  = 1 (219 UM)

Conclusion:
Based on a total study sample of n=161, the calculated power is 0.13.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and discontinuing AD treatment.

CYP2C19 NM vs. IM/PM -Discontinuing Power calculation -Odds of discontinuing
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of discontinuing AD treatment (Y=1) when being a CYP2C19 NM patient (X=0): Odds ratio (OR) being calculated according to the following formulas: Proportion of cases for which X=1 (CYP2C19 IM/PM) within the total sample size (n=192): Based on a total study sample of n=192, the calculated power is 0.06.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and discontinuing AD treatment.

CYP2C19 NM vs. UM -Switching Power calculation -Odds of switching
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of switching AD treatment (Y=1) when being a CYP2C19 NM patient (X=0): Odds ratio (OR) being calculated according to the following formulas: Proportion of cases for which X=1 (CYP2C19 UM) within the total sample size (n=209): Based on a total study sample of n=209, the calculated power is 0.08.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and switching AD treatment.

CYP2C19 NM vs. IM/PM -Switching Power calculation -Odds of switching
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of switching AD treatment (Y=1) when being a CYP2C19 NM patient (X=0): Odds ratio (OR) being calculated according to the following formulas: Based on a total study sample of n=256, the calculated power is 0.11.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and switching AD treatment.

CYP2D6 NM vs. IM/PM -Discontinuing Power calculation -Odds of discontinuing
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of discontinuing AD treatment (Y=1) when being a CYP2D6 NM patient (X=0): Odds ratio (OR) being calculated according to the following formulas: Based on a total study sample of n=522, the calculated power is 0.27.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2D6 metabolizer status and discontinuing AD treatment.

CYP2D6 NM vs. IM/PM -Switching Power calculation -Odds of switching
The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of switching AD treatment (Y=1) when being a CYP2D6 NM patient (X=0): Odds ratio (OR) being calculated according to the following formulas: The following definitions and formulas are needed to perform a post-hoc power calculation: Probability of discontinuing AD treatment (Y=1) when being a CYP2C19 NM patient (X=0): • Pr( = 1|  = 1)  0 =  1 Odds ratio (OR) being calculated according to the following formulas: Based on a total study sample of n=161, the calculated power is 0.08.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and discontinuing AD treatment.Based on a total study sample of n=146, the calculated power is 0.05.Compared to a standard power of 0.8, the current study is therefore considered underpowered to investigate an association between CYP2C19 metabolizer status and discontinuing AD treatment.